SP #9: Structural and Functional Changes related to Parkinson’s Disease

Structural and Functional Changes related to Parkinson’s Disease

Significance:

Parkinson's disease (PD) is an age-related neurological disorder that affects about one million Americans' quality of life by causing motor and other dysfunctions, despite patients being on the best treatments available. Understanding the exact cause, and assessing a treatment to slow, or stop, the progression of the disease are hindered by the lack of a widely available, yet reliable, marker for disease progression. The goal of this project is to establish MRI measurements as such a marker, thereby leading to a better understanding of the causes of PD and improved assessment of potential neuroprotective agents in PD.

Compared to ongoing efforts to assess functionality and cell loss with PET and SPECT, structural volumetric imaging can reflect in vivo macroscopic atrophy (caused by cell loss), is less likely to be influenced by purely symptomatic treatments, can assess extranigral/nondopaminergic systems, and is widely available. Yet this ap­proach has not been as exhaustively explored because of the difficulty in relating atrophic changes to a specific mechanism, and because of inconsistent findings in prior structural imaging studies in PD. The latter may be a result of cross-sectional designs, small sample sizes, and/or imaging analysis methods with low relia­bility.

Aims:

Our goal is to pursue structural and functional imaging studies in PD [1-4] with MRI. In these studies, we will establish the differential roles of DTI and R2* in PD detection and progression as well as test Fe-related proteins in body fluids as biomarkers. In our preliminary data, we have observed brain atrophic changes focally (e.g. BG structure) and globally in PD patients relative to normative age-matched controls. We will continue to observe structural changes in PD patients to characterize the lateralization and time-course of longitudinal volumetric changes of lateral ventricles and select BG regions during the course of PD progression in relation to PD motor asymmetry and duration.

Approach:

Supported by strong preliminary data, our central hypothesis is that PD patients undergo significant brain atrophic changes focally (e.g., in BG structures) and globally relative to a normative age-matched sample. Not only can these changes be quantified reliably using high resolution MRI coupled with sophisticated analysis techniques, but they may have functional implications that are relevant to PD at both the clinical and heuristic levels. We propose to do longitudinal studies of numerous PD subjects within 10 years of clinical diagnosis, as well as controls (matched in age, gender, handedness, & education).

We have three funded projects relying heavily on MRI to assess neuroanatomy and function in Parkinson’s disease and related groups (including welders with high exposure to Mn for R01ES019672 [5]), all of which will benefit from CAI2R innovations.  The particular aims of these projects are as follows:

U01 NS082151: 1) Establish the differential roles of DTI and R2* in PD detection and progression; 2) Demonstrate that nigrostriatal DTI and R2* differentiate PD from parkinsonian syndromes; 3) Interrogate Fe-related proteins in body fluids as biomarkers; 4) Obtain MRI biomarker and postmortem pathological correlation data. Successful conclusion of this study will yield valid markers for both detection of PD assessment of progression that can be integrated into and hopefully impact disease-modifying clinical trials within the foreseeable future.

R01 NS060722: 1) Establish the age trend of lateral ventricle enlargement and BG regional atrophy in PD patients compared to controls; 2) Characterize the lateralization and time-course of longitudinal volumetric changes of lateral ventricles and selected BG regions during PD progression in relation to PD motor asymmetry and duration; 3) Explore the potential of the volumetric measures of different structures of interest as markers of individual aspects of PD motor and non-motor dysfunction during disease progression; and 4) Explore the interrelationships of changes among different brain regions and PD-related functional changes.

R01 ES019672: 1) Validate that the MRI T1 measurements provide a reliable biomarker of Mn exposure in specific brain regions [e.g., OB, BG and FL, etc.] in humans. 2) Delineate the functional consequences of region-specific Mn accumulation in the brain. 3) Explore Fe-Mn interactions in brain and their functional consequences.

BTRC Resources Utilized:

TR&D #1: This study (including all three funded projects) will benefit greatly from TR&D #1 of the BTRC. Many of the sequence types utilized (DTI, SWI, quantitative T1 and T2 measurements, fMRI) are already targets of the TR&D #1 research plan. More rapid acquisition will both reduce the stress on subjects and provide better registration of data sets.  Advanced acquisition and reconstruction approaches from the BTRC will enable higher quality data less susceptible to motion or B0-related artifacts.  Note that BTRC investigator (and TR&D #2 co-PI) Dr. Collins was previously a colleague of SP PI Dr. Huang’s at in Pennsylvania, and in addition to TR&D #1 staff, Dr. Collins will serve as a liason for this SP.

Principal Investigator: 

Sponsors

Latest Updates

10/31/2017 - 11:54
10/31/2017 - 11:37

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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